Pain is the most commonly cited medical problem in this country. It affects over 60 million Americans and costs billions of dollars in health care and lost productivity annually. While there are opioid treatments for pain, they have several drawbacks, including the development of tolerance and lack of effect on some types of chronic pain. Thus, there is a medical need and commercial opportunity for the development of alternative non-opioid treatments for pain. Recent research indicates that metabotropic glutamate receptors (mGluRs) located in the dorsal horn of the spinal cord are involved in the processing of nociceptive information. In particular, antagonists of the mGluRl receptor subtype have potential as clinically effective anti-nociceptive agents. The venoms of marine cone snails are unique collections of small peptides with biological activity at a number of ion channels and neurotransmitter receptors. Many of these conopeptides are notable for their potency and molecular specificity within a receptor family. The goal of this phase I proposal is to identify conopeptides that are potent and selective antagonists of the mGluRl subtype of glutamate receptor. Compounds identified in these initial assays will be characterized in animal models of chronic pain in phase II of this study.